Efficacy and Safety of Sarilumab in COVID-19: A Systematic Review

Background It has been found that there is overactivation of immune response in patients with COVID-19. Several studies are going on to assess the role of immunomodulation. IL-6 antibodies such as tocilizumab have been found to have efficacy in the treatment of COVID-19. We aim to assess the role of sarilumab in the treatment of COVID-19 through this review. Main Body. Functional outcomes were assessed on the basis of PaO2/FiO2 ratio, mortality, and ventilation. Adverse events of studies were also noted. Five studies were included in the study. There was improvement in PaO2/FiO2 ratio, reduction in the mortality of the patients, and less number of patients were on ventilation, but there were no significant differences among the comparison and sarilumab group. Sarilumab did not have notable adverse events and can be considered a safe drug. Conclusion Sarilumab is a safe drug with good clinical outcomes in patients with COVID-19 and, hence, could be used as an alternative regimen for the treatment. Further prospective studies exploring the relations with baseline biomarkers of inflammation commonly measured such as C-reactive protein and IL-6 would be necessary for a correlation with the treatment.


Background
e World Health Organization (WHO) has declared COVID-19 as a global pandemic which was first identified in Wuhan, China, in December 2019 [1]. More than 164 million have been infected with more than 3 million deaths worldwide, which is on exponential rise [2] (Figure 1). e range of symptoms of COVID-19 varies from asymptomatic to pneumonia-like symptoms and may even lead to multiorgan failure and death. As per the Centers for Disease Control and Prevention (CDC), the clinical manifestations of COVID-19 includes fever or chills, cough, shortness of breath or difficulty breathing, muscle or body aches, fatigue, headache, sore throat, a new loss of taste or smell, congestion or runny nose, nausea or vomiting, and diarrhea [3]. Double B.1.617 (E484K and L452R) and triple mutant (V382L) strains of single-stranded RNA virus have been reported from twenty-one nations around the globe, and these patients have presented with increased severity of symptoms as compared to previous strains and have been classified as variants of concern by the World Health Organization [4].
It is assumed that COVID-19 results in Cytokine Release Syndrome (CRS), which leads to dysregulation and excessive increase in immune response of the host even though the exact mechanism remains unknown [5]. Many proinflammatory cytokines are involved in CRS, and among them, Interleukin-6 (IL-6) is the most important. Increase in the circulating level of proinflammatory cytokines (IL-1 and IL-6) and chemokines results in adverse clinical outcomes of which increasing IL-6 is a poor prognostic factor [6].
ere is no definitive treatment for this condition, and hence, symptomatic management is the only treatment so far.
Sarilumab, initially approved for use in rheumatoid arthritis, is a human monoclonal antibody which acts against IL-6 receptors. Additionally, this drug has been considered for off-label use in the treatment of COVID-19. Recent trials have reported that it reduces the duration of hospital stay, and it has been considered as a safe drug.
ere is no concrete evidence among the trials to have its efficacious role in the treatment of COVID-19. To our knowledge, no systematic review is available to assess the role of sarilumab. In this review, we aim to analyze the role of the immunomodulator, sarilumab, in the treatment of COVID-19 patients.

Study Identification.
e systematic search was conducted in online databases PubMed, https://clinicaltrials. gov, and EMBASE using the keywords "Sarilumab," "COVID," and "SARS COV-2," connected with "OR" and "AND" Boolean operators, while the article search was conducted from 2018 onwards. e reference list of included trials and articles were also searched to identify additional articles. e abstract was screened using microsoft excel 2013 (windows version) followed by full-text screening. For those articles with partial information, concerned authors were contacted via e-mail. For future analysis, we retrieved all the references in all manuscripts. Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) [7] and protocol for reviews detailed in the Cochrane Handbook for Systematic Reviews of Interventions [8] were followed for reporting the article. e first active search was performed on 2 March 2021, while the last was performed on 10 March 2021.

Inclusion Criteria.
Studies were selected on the basis of the following criteria: (i) Patients with COVID-19, including all its stages (ii) Any study design (randomized controlled trials with double-blindfold/observational studies/case-control studies) on humans reporting clinical outcome on sarilumab (iii) Patients who received sarilumab as an experimental drug

Exclusion Criteria.
Studies were excluded on the basis of the following criteria.
(i) Study on other experimental animals (ii) Trials which did not use sarilumab as an experimental drug (iii) Articles that were not available in English (iv) All other forms of articles such as case reports Adverse reaction was recorded for all the studies included. Extracted data were checked by another author (BSP), and disagreement was resolved by discussion with other authors (RD and BK).

Quality Assessment.
We evaluated the following items in the assessment: (1) clarity of the study objectives; (2) whether the study period (start date and end date) was stated clearly; (3) whether the description of the patient selection criteria was clear or not; (4) study was conducted in multicenter or not; (5) the stated sarilumab treatment method and dose; (6) whether the baseline equivalence groups were clearly considered; (7) the definition of the primary outcome (PaO 2 /FiO 2 ratio or overall mortality or ventilation requirement) prior to the study; (8) if the follow-up period was long enough (months); (9) whether a clear hazard ratio (HR) with 95% confidence intervals (95% CI) was stated; and (10) the limitations of each study were considered. We did not use quality assessment as exclusion criteria.
According to the quality items used in each study (score range 0-10), the papers were assessed.

Efficacy Measurement.
e functional outcomes of patients were analyzed under the following subheadings: (i) Partial pressure of arterial oxygen (PaO 2 )/fraction of inspired oxygen (FiO 2 ) ratio: it is the ratio of arterial oxygen partial pressure to fractional inspired oxygen. It helps to determine how well oxygen is moving from the lungs to blood [9]. (ii) Mortality: mortality was determined by using different scales such as the six-category/seven-category ordinal scale. (iii) Need of mechanical ventilation (noninvasive ventilation (NIV) and invasive mechanical ventilation (MV)).

Data Synthesis.
All identified studies were included in the narrative summary with summary tables for characteristics. In addition, data were summarized using descriptive statistics. We used means for continuous variables and frequencies and percentages for dichotomous variables.

Literature Search.
e literature search resulted in 90 studies. After the complete screening process of titles, abstracts, and full texts, 85 studies did not meet the eligibility criteria. Finally, five articles with different study designs that met the criteria were included in the review. A description of study selection is shown in the PRISMA flow diagram in Figure 2.

Quality Assessment Results.
With the use of the quality assessment tool, individual questions of the study were answered in "yes" or "no" with 1 point for "yes" and no points for "no." e total score was added for the individual study as denoted in the respective columns. e quality of the five included studies was fair with an average quality score of 6.6 and a median score of 7 (range 3-10) (  [10]. e median PaO 2 /FiO 2 at baseline for all patients was 122 (range 83-240), and 8 of 15 (53.3%) were intubated at the time of administration of sarilumab [11]. e median baseline PaO 2 /FiO 2 for patients who responded to sarilumab was 121 mm of Hg. e median baseline PaO 2 /FiO 2 was 178 mm of Hg in patients who did not respond to sarilumab [11].
ere was improvement in oxygenation as indicated by the Horovitz index by ≥ 50 for 48 hours [12]. PaO 2 /FiO 2 was associated with clinical improvement in both univariate and multivariate analysis and was found to be an independent predictor for clinical improvement in multivariate analysis (HR: 0.87; 95% CI 0.86 to 0.99; P � 0.03) [10]. ere was a negative insignificant correlation (r � −0.0005 and P � 0.98) between PaO 2 /FiO 2 ratio and lung consolidation [10].

Ventilation.
Six of 28 patients of the sarilumab group and 7 of 28 patients of the control group (P � 0.99) were on mechanical ventilation [10]. Among eight patients who required mechanical ventilation prior to administration of sarilumab, pulmonary function was improved in 3 of them and 1 died after being extubated due to a massive embolism [11]. e details of invasive and noninvasive mechanical ventilation in study by Gremese et al. are shown in Table 3.

Adverse Effects.
In a study by Montesarchio et al., 1 patient developed grade II thrombocytopenia [11]. 12/28 patients (43%) in the sarilumab group and 10/28 patients (36%) in the control group reported adverse events between baseline and day 28. Six patients (21%) in the sarilumab group and five (18%) in the control group had bacterial infections in the ICU with polymicrobial infection in 4/6 cases in the sarilumab group [10]. e rates of treatmentemergent adverse events, infection, and treatment-emergent adverse events leading to death were similar among the treatment groups [14].

Discussion
An IL-6 receptor antibody, tocilizumab, initially approved for rheumatoid arthritis has been approved for off-label use against COVID-19. Likewise, sarilumab, another IL-6 antibody, is also under trials for the treatment of COVID- 19. ere was improvement in the respiratory function as measured by PaO 2 /FiO 2 ratio with the use of sarilumab [10,11]. But, the improvement in PaO 2 /FiO 2 ratio was not Interdisciplinary Perspectives on Infectious Diseases statistically significant with the comparison group. Tocilizumab has already been established as an effective drug in improving oxygen transfer from lungs to blood [15]. Mortality assessment on a 6-or 7-point ordinal scale determined that the number of deaths was decreased but it was not statistically significant among the sarilumab group and comparison group [13,14]. e probable reason for these could be concomitant the use of other medications such as dexamethasone, lopinavir, and heparin. Similar to sarilumab, lopinavir also reported similar mortality rates among lopinavir and standard care groups [16]. Furthermore, dexamethasone reduced the death by one-third and one-fifth among COVID-19 patients who were on mechanical ventilation and without invasive mechanical ventilation, respectively, in a RECOVERY trial [17]. But, the same trial did not report a reduction in mortality for the patients who were not on respiratory support [17]. Early administration of cytokine modulation therapy    Interdisciplinary Perspectives on Infectious Diseases (Tocilizumab), before the onset of symptoms, deteriorates the onset of cytokine storm. Hence, the timing of IL-6 therapy may also have affected the mortality. Immunomodulation is thought to be beneficial in serious cases of COVID-19. When sarilumab was given in patients with severe COVID-19 in the ICU, it was found to have significant improvement in health condition, and they were transferred to medical wards [13]. Suppression of IL-6 alone may not be sufficient to explain the inflammatory phase of this disease because of the involvement of other inflammatory cytokines and chemokine. Tocilizumab found no significant improvement in reducing disease severity and time to intubation or death in a randomized controlled trial [18]. Similar findings were observed in a trial of dexamethasone versus usual care in patients with COVID-19; this trial suggested survival benefits that were associated with the intensity of respiratory support [17]. Sarilumab may reduce the number of days of hospitalization. Less number of patients went on mechanical ventilation or death in EMPACTA, randomized placebo-controlled study for tocilizumab [19]. Sarilumab is a safe drug with less treatment-emergent adverse effects. Most of the studies did not report the adverse effects, and among the studies that reported adverse effects, treatment-emergent adverse events were not available. Tocilizumab, another IL-6 antibody, was found to be safe, but it showed an increase in the incidence of adverse infectious events such as bacterial and fungal infections with no better outcomes with 400 mg dose compared with patients treated with a single dose of tocilizumab 400 mg [20]. e included studies were conducted for a shorter duration, and hence, long-term adverse events were not available.
Our review had several limitations. Firstly, patients included in most of the studies were not recruited on clinical markers of inflammation or worse prognosis. Concomitant use of other therapies along with sarilumab also had interfered with the outcomes. Efficacy endpoints that were used to assess may be insensitive for a wide range of COVID-19 because its symptom ranges from asymptomatic to respiratory failure. Also, the functional scale to assess mortality was different across different studies. e sample sizes of the included studies were small, and the duration of the study was also short. Finally, most of the studies were open label, were not randomized, and were conducted in a singlecenter setting.

Conclusions
Sarilumab is a safe drug with good clinical outcomes in patients with COVID-19 and, hence, could be an alternative regimen for the treatment. Further prospective studies with larger sample size and long-term follow-up are required to assess the efficacious role of the IL-6 antagonist. Exploring relations with baseline biomarkers of inflammation such as C-reactive protein (CRP) and IL-6 would be necessary for a correlation with the treatment.